JP2002539261A - Pharmaceutical composition containing pyrimidine derivative and cyclodextrin - Google Patents

Abstract

(57) [Summary] a) Formula (I): 1,2,4-triazolo [1,5-a] pyrimidine derivatives or pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof, and b) a cyclodextrin Pharmaceutical composition. These compositions are useful as neuroprotective agents for treating neurological disorders such as migraine, seizures and / or epilepsy and / or preventing conditions such as stroke, brain trauma, head trauma and bleeding in animals including humans. It is.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising a 1,2,4-triazolo [1,5-a] pyrimidine derivative and cyclodextrin, as well as migraine, seizures, neuropathy (eg epilepsy) and / or nerve damage. It relates to its use in the treatment and / or prevention of associated conditions such as stroke, brain trauma, head trauma and bleeding.

Although cerebral ischemia is a major cause of morbidity and mortality in Western societies, pharmacotherapy for this condition is still inadequate and prevention remains the most effective treatment (De Deyn
, P. P. , De Reuck, J. et al. Deberdt, W .; , Vlietin
ck, R.A. , Orgogozo, J. et al. M. (1997) Treatment
of accurate ischemic stroke with piston
tam. (Stroke, 28, 2347-2352). If an agent could be provided that would provide neuroprotection to stroke patients with more advanced ischemic damage than to prevent the risk of ischemic damage, it would be very effective in treating this disease.

[0003] WO 95/10521 (Knoll AG) has the formula A:

[0004]

Embedded image[Wherein, R₁Is H or (optionally one of halo, cyano, hydroxy or amino
C)_1-6Alkyl, C_1-6Alkoxy or C_1-6A
Rucanoyl represents one type of group₂And R₃Are independently H or (optionally halo,
C substituted with one or more of ano, hydroxy or amino)_1-6Alkyl, C_{1 -6} Alkoxy, C_1-6Alkanoyl, C_1-6Alkylthio, C_1-6Al
Killsulfinyl or C_1-6R represents an alkylsulfonyl group;₄When
R₅Are independently H, C_1-6Represents alkyl or R₄And R₅Together
Together with the carbon atom to which they are attached_3-6Represents cycloalkylidene (each
Alkyl or cycloalkylidene is optionally halo, cyano, hydroxy, amino
Or C_1-6Alkyl).₆, R₇And R ₈ Is independently H, halo, hydroxy, mercapto, nitro, cyano or (in some cases
Further substituted with one or more halo, cyano, hydroxy or amino,
If there is a child, optionally one or more C_1-6C substituted with alkyl) _1-6 Alkyl, C_1-6Alkanoyl, C_1-6Alkoxy, C_2-6Arco
Xycarbonyl, carboxy, C_1-6Alkanoyloxy, C_1-6Alkyl
Thio, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl, C_1-6 Alkylsulfonylamino, sulfamoyl, carbamoyl, C_2-6Alkyl
Carbamoyl or C_1-6Represents one kind of alkanoylamino group],
Methods for their manufacture, and with seizures, neuropathy (eg epilepsy) and / or nerve damage
In the treatment and / or prevention of conditions (eg, stroke, brain trauma, head trauma and bleeding)
Its use has been described. WO98 / 07724 (Knoll AG)
Methods for making these compounds are disclosed.

However, compounds of formula A have the disadvantage that they are insoluble in water and have a short plasma half-life in humans after oral solid administration. Therefore, it is believed that these compounds can only be used to treat stroke. Surprisingly, the present invention solves these problems and provides a feasible method for effective stroke treatment.

The present invention relates to: a) Formula I:

[0007]

Embedded image Wherein R ₁ is H or _one of C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkanoyl groups (optionally substituted with one or more halo, cyano, hydroxy or amino). Wherein R ₂ and R ₃ are independently H or C _1-6 alkyl (optionally substituted with one or more halo, cyano, hydroxy or amino), C _1-6 alkoxy, C _1-6 alkanoyl, Represents one of C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl or a hydroxy group, and R ₄ and R ₅ independently represent H, C _1-6 alkyl, or R ₄ and R ₅ halo when a represents (each alkyl or cycloalkylidene is C _3-6 cycloalkylidene together with the carbon atoms to which they are attached together, cyano, hydroxy
R ₆ , R ₇ and R ₈ may be independently H, halo, hydroxy, mercapto, nitro, cyano or (optionally halo, cyano), optionally substituted with one or more amino or C _1-6 alkyl. , hydroxy or substituted amino of 1 or more, when a nitrogen atom present is substituted with one or more C _{1 -6} alkyl optionally nitrogen atom) C _1-6 alkyl, C _{1 -6 alkanoyl, C 1-6 alkoxy, C 2-6} alkoxycarbonyl, _{carboxy, C 1-6 alkanoyloxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6} alkylsulfonylamino, sulfamoyl, _carbamoyl, a _{C 2-6} 1 or alkylcarbamoyl or _{C 1-6} alkanoylamino group table Compounds of] and (a pharmaceutically acceptable salt, solvate, racemate, enantiomer, diastereoisomer including isomers and mixtures thereof), b) providing a pharmaceutical composition comprising a cyclodextrin.

[0008] It will be understood that any of the groups described herein containing chains of three or more carbon atoms may be straight or branched. For example, an alkyl group can include n-propyl and isopropyl as propyl, and can include n-butyl, sec-butyl, isobutyl and tert-butyl as butyl. In the present specification, the total number of carbon atoms is specified for the predetermined substituent. For example, C _1-6 means an alkyl group having 1 to 6 carbon atoms. As used herein, the term "halo" refers to fluoro, chloro, bromo, and iodo. The term "optionally substituted" as used herein, unless a substituent is listed immediately after, is optionally substituted with one or more groups selected from halo, cyano, hydroxy and amino. Means that. When the phenyl ring substituents R ₆ , R ₇ and R ₈ are other than H, the substituent may be substituted on any H bonded to a carbon atom in the ring, and at any such position on the ring, ie 2,
It can be placed in three, four and / or five positions.

Suitably, the composition is a mixture of a compound of formula I and cyclodextrin. Preferably, the composition comprises a complex of the compound of formula I and cyclodextrin. Suitably, the ratio of compound of formula I to cyclodextrin in the conjugate ranges from 0.1 to 1: 1 to 0.1.

The complex is formed at a temperature in the range of 10-100 ° C. to form a mixture of the compound of formula I or a pharmaceutically acceptable salt thereof with cyclodextrin and water to form a suspension or solution, It is appropriate to produce by dehydration by a method such as granulation, spray drying, drum drying or freeze drying. Spray drying is preferred because a free flowing granular solid is obtained. Fluid bed spray drying is particularly preferred.

The mixture of the compound of formula I and cyclodextrin or the complex of the compound of formula I and cyclodextrin can be formulated into any of the well-known solid pharmaceutical preparations such as tablets, capsules, granules, powders and the like. The composition can include a foaming agent, a buffering system, a sweetening agent, a flavoring agent, a coloring agent, and the like, and the diluent is a carrier such as a water-soluble saccharide (eg, dextrose, lactose or sucrose).

[0012] For therapeutic use, the compositions of the present invention can be formulated into pharmaceutical compositions for oral, rectal or parenteral administration. That is, the therapeutic composition of the present invention can take any form of a pharmaceutical composition known for such treatment. The composition provides controlled release of the active compound;
For example, it can be formulated in a manner known to those skilled in the art to provide fast or sustained release. Pharmaceutically acceptable carriers suitable for use in such compositions are well-known in the pharmaceutical art. The compositions may contain from about 0.1% to about 99% by weight of the active compound, and are generally prepared in a unit dosage form. The unit dose of active ingredient can be from about 1 mg to about 1 mg.
000 mg is preferred, and about 1 mg to about 500 mg is more preferred. Excipients used in the manufacture of these compositions are those known in the pharmaceutical art.

The compositions of the present invention are preferably administered orally in a pharmaceutical form known for such administration. Dosage forms suitable for oral administration include tablets, pills, capsules, caplets,
Examples include multiparticulates (eg, granules, beads, pellets and microcapsule particles), powders, elixirs, syrups, suspensions and solutions.

For example, solid oral dosage forms such as tablets can be prepared by mixing the pharmaceutical composition of the present invention with one or more of the following components or a mixture thereof.

Inert diluents such as calcium carbonate, calcium sulfate, compressible sugar, confectionery sugar, dextrate, dextrin, dextrose, dicalcium phosphate · 2
Hydrate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol,
Microcrystalline cellulose, polymethacrylate, potassium chloride, powdered cellulose, α-starch, sodium chloride, sorbitol, starch, sucrose, spherical sugar, talc and tricalcium phosphate; disintegrants such as alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, colloidal Silicon dioxide, croscarmellose sodium, crospopidone, guar gum, aluminum magnesium silicate,
Methylcellulose, microcrystalline cellulose, potassium polacrilin, powdered cellulose, α-starch, sodium alginate, sodium starch glycolate, starch (eg, corn starch) and agar; lubricants such as calcium stearate, glyceryl monostearate, palmitostearic acid Glyceryl, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate; binders, such as gum arabic, alginic acid , Carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxymethylcellulose, hydr Roxypropyl cellulose,
Hydroxypropyl methylcellulose, liquid glucose, aluminum magnesium silicate, maltodextrin, methylcellulose, polymethacrylate, povidone, alpha starch, sodium alginate, starch (eg, corn starch), zein, sugars (eg, sucrose, molasses and lactose), and natural and synthetic Gums (e.g., Irish moss extract, polyethylene glycol, waxes, microcrystalline cellulose and polyvinylpyrrolidone); coloring agents, e.g., pharmaceutically acceptable conventional pigments; sweetening and flavoring agents; preservatives; One or more pharmaceutically acceptable pairs (eg, acid and carbonate or bicarbonate pairs) that foam when added to water to facilitate dissolution; for preparing oral dosage forms by known methods, such as tableting. Other optional ingredients known in the art.

Solid oral dosage forms may be formulated in a manner known to those skilled in the art to provide sustained release of the compounds of the present invention. Depending on the type of active compound, a film-coated solid oral dosage form containing the composition of the present invention may be advantageous. Various materials may be coated, such as, for example, shellac and / or sugar, or otherwise added, to alter the physical form of the oral dosage form. For example, tablets or pills may be enteric coated, if desired, using known methods, for example using cellulose acetate phthalate and / or hydroxypropylmethyl cellulose phthalate.

Capsules or caplets (eg, hard or soft gelatin capsules) containing the compositions of the present invention (with or without excipients such as fatty oils) can be prepared by conventional methods, and if desired, Enteric coating may be performed by a known method. The contents of the capsule or caplet may be formulated in a known manner to provide sustained release of the active compound.

A particularly preferred oral liquid dosage form is a therapeutically effective amount of a compound of formula I above or a pharmaceutically acceptable salt, solvate, racemate, enantiomer, diastereoisomer and mixture thereof, A pharmaceutical formulation that is an aqueous solution containing a sufficient amount of cyclodextrin to dissolve the compound of I. Cyclodextrin is β-
Cyclodextrin is preferred. Liquid oral dosage forms may further comprise one or more sweetening agents, flavoring agents, preservatives and mixtures thereof.

The compositions of the present invention may be formulated into granules or powders with or without additional excipients. Granules or powders may be taken directly by the patient or added to a suitable liquid carrier (eg, water) prior to ingestion. Granules or powders may contain disintegrants (eg, pharmaceutically acceptable effervescent couples formed from acids and carbonates or bicarbonates) to facilitate dispersion in the liquid medium.

The oral dosage forms each comprise about 1 mg to about 500 mg (eg, 10 mg, 50 mg, 1 mg,
(00 mg, 200 mg, 400 mg or 500 mg) of active compound.

The compositions of the present invention may be administered rectally in a pharmaceutical form known for such administration (eg, a suppository with a solid fat, semi-synthetic glyceride, cocoa butter or polyethylene glycol base).

The compositions of the present invention may be administered parenterally in pharmaceutical forms known for such administration (eg, sterile solutions in suitable solvents), for example, by intravenous injection.

The compositions of the present invention may be administered by continuous infusion from an external source (eg, intravenous infusion) or a source of the compound located in the body. The internal source may be continuous release (eg, by osmotic pressure) from an implanted reservoir containing the compound to be injected, or an implant. The amount of active compound contained in the body source should be selected to provide a therapeutically effective amount of the compound for prolonged release.

A particularly preferred embodiment of the invention for parenteral administration, especially for intravenous injection, is a therapeutically effective amount of a compound of formula I above or a pharmaceutically acceptable salt, solvate, racemate, enantiomer thereof. , A diastereoisomer and a mixture, and an aqueous solution containing a sufficient amount of cyclodextrin to dissolve the compound of formula I.

Depending on the composition, it may be advantageous to use the active compounds in very small particle form, for example as obtained by fluid energy milling.

In the above compositions, the active compound may be combined with other compatible pharmacologically active ingredients.

Use of the composition of the present invention as a neuroprotective agent for preventing a condition such as stroke;
Designated for treatment of neurological disorders such as seizures and epilepsy. The therapeutic activity of the composition has been demonstrated by various in vivo pharmacological tests in standard laboratory animals.

Accordingly, another aspect of the present invention provides a method for treating a neurological disorder such as seizures and / or epilepsy and / or a neuroprotective method for preventing a condition such as a stroke in animals including humans,
The method comprises administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an active compound of a compound of Formula I and cyclodextrin. Therefore, the composition of the present invention is useful as a neuroprotective agent for suppressing neurological disorders such as seizures and / or epilepsy and / or preventing conditions such as stroke in animals including humans. The compositions of the present invention are also useful for treating and preventing migraine.

The precise dosage of the active compound in the treatments outlined above will depend on a number of factors, such as the severity of the condition, the age of the patient and the medical history, and will be determined by the administering pharmacist, physician or veterinarian. A suitable daily dose of the active compound when administered to a human is generally about 1 mg to about 5000 mg, more usually about 5 mg to about 10 mg.
00 mg is administered once or twice a day. Oral administration or intravenous infusion is preferred.

The composition of the present invention may be used as a neuroprotective agent for treating neurological disorders such as seizures and / or epilepsy and / or preventing conditions such as stroke in animals including humans, and for treating and preventing migraine. May also be used in combination therapy with one or more other compounds that are effective for the treatment. The term therapy, as used herein, refers to active compounds and therapeutics as neuroprotective agents for preventing the development of neurological disorders such as epileptic seizures in animals, including humans, or for preventing conditions such as stroke. It will be understood that this includes the prophylactic use of a pharmaceutical composition containing a pharmaceutically effective amount of the active compound. Pharmaceutical compositions containing the active compound and a therapeutically effective amount of the active compound can be used to provide a local and / or systemic therapeutic effect.

Yet another aspect of the invention is the treatment of neurological disorders such as seizures and / or epilepsy and / or neuroprotection and / or treatment of stroke to prevent conditions such as stroke in animals including humans. There is provided the use of a composition of the invention in the manufacture of a medicament for prevention.

A specific compound of formula I is 7- [1- (4-fluorophenoxy) ethyl] -1,2,4-triazolo [1
, 5-a] pyrimidine, 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,
5-a] pyrimidine, 7- [1- (4-bromophenoxy) ethyl] -1,2,4-triazolo [1,
5-a] pyrimidine, 7- [1- (4-cyanophenoxy) ethyl] -1,2,4-triazolo [1,
5-a] pyrimidine, 7- [1- (4-trifluoromethylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-methoxyphenoxy) ethyl ] -1,2,4-triazolo [1
, 5-a] Pyrimidine, 7- [1- (4-trifluoromethoxyphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-acetylphenoxy) Ethyl] -1,2,4-triazolo [1
, 5-a] pyrimidine, 7- {1- [4- (methylthio) phenoxy] ethyl} -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-methylsulfinylphenoxy) ) Ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-methylsulfonylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine 7- {1- [4- (ethylthio) phenoxy] ethyl} -1,2,4-triazolo [1,5-a] pyrimidine; 7- [1- (3-chlorophenoxy) ethyl] -1,2 , 4-triazolo [1,
5-a] pyrimidine, 7- [1- (2,4-difluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (2,4-dichlorophenoxy) ) Ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (3,4-dichlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] Pyrimidine, 7- [1- (2-chloro-4-fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-chlorophenoxy) ethyl]- 2-methyl-1,2,4-triazolo [1,5-a] pyrimidine, 7- (4-chlorophenoxymethyl) -1,2,4-triazolo [1,5-a]
Pyrimidine, 7- [1- (4-chlorophenoxy) -1-methylethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-chlorophenoxy) propyl]- 1,2,4-triazolo [1
, 5-a] pyrimidine and 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,
5-a] pyrimidin-5-ol and its stereoisomers and pharmaceutically acceptable salts thereof.

Specific examples of stereoisomers of the compounds of formula I include (+)-7- [1- (4-fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, (-)-7- [1- (4-Fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, (+)-7- [1- (4-chlorophenoxy) ethyl ] -1,2,4-Triazolo [1,5-a] pyrimidine, (-)-7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] Pyrimidine, (+)-7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-ol, and (-)-7- [1- (4-Chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pirimi Zin-5-ol and pharmaceutically acceptable salts thereof.

A preferred compound of formula I is 7- [1- (4-chlorophenoxy) ethyl] -1,
2,4-triazolo [1,5-a] pyrimidine and 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-ol, , Its racemates, enantiomers and mixtures thereof and pharmaceutically acceptable salts thereof. More preferred compounds of formula I are (R) -7- [1
-(4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a]
Pyrimidine and (S) -7- [1- (4-chlorophenoxy) ethyl] -1,2
, 4-Triazolo [1,5-a] pyrimidine and pharmaceutically acceptable salts thereof. The most preferred compound of formula I is (R) -7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine and a pharmaceutically acceptable salt thereof. is there. (R) -7- [1- (4-chlorophenoxy) ethyl] -1,
The free base of 2,4-triazolo [1,5-a] pyrimidine has a negative optical rotation.

The compounds of the formula I are described in WO 95/10521 (Knoll AG) and WO 98/0
7724 (Knoll AG).

Suitably, the cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin. Available β-cyclodextrins include β-cyclodextrin, methyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-
β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin,
2,3-dihydroxypropyl-β-cyclodextrin, trimethyl-β-cyclodextrin, 6-O-α-D-glucosyl-β-cyclodextrin, 6
-O-α-D-maltosyl-β-cyclodextrin, dimaltosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltotriosyl-
β-cyclodextrin, carboxymethyl-β-cyclodextrin, carboxyethyl-β-cyclodextrin, heptakis- (2,6-di-O-methyl) -β-cyclodextrin, heptakis- (2,3,6-tri -O-methyl)
-Β-cyclodextrin, β-cyclodextrin sulfobutyl ether (described in U.S. Patent Nos. 5,376,645 and 5,134,127). Available γ-cyclodextrins include 2-hydroxypropyl-γ-cyclodextrin. The cyclodextrin is preferably β-cyclodextrin. The cyclodextrin is more preferably methyl-β-cyclodextrin or 2-hydroxypropyl-β-cyclodextrin. Most preferably, the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.

A preferred embodiment of the present invention comprises a) a therapeutically effective amount of a compound of formula I above,
) A pharmaceutical composition in the form of an aqueous solution containing β-cyclodextrin.

Surprisingly, compounds of formula I, in particular (R) -7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine and 2- Compositions containing hydroxypropyl-β-cyclodextrin are particularly advantageous because of their higher solubility and lower toxicity compared to compositions containing other cyclodextrins. Such compositions provide aqueous solutions that can be administered to stroke patients by intravenous injection or continuous infusion. Such compositions can provide a significant advance in the treatment of stroke where rapid treatment is essential. These compositions are considered to be particularly selected from the possible combinations of the compounds of the formula I and cyclodextrins with unexpected and advantageous properties which cannot be obtained in other possible combinations.

A more preferred embodiment of the present invention is a pharmaceutical composition in the form of an aqueous solution, comprising a) a therapeutically effective amount of a compound of formula I above and b) 2-hydroxypropyl-β-cyclodextrin.

The most preferred embodiment of the present invention is a) a therapeutically effective amount of 0.1-30% w /
and v) a concentration ranging from 5 to 75% w / v.
It is a pharmaceutical composition in the form of an aqueous solution containing -hydroxypropyl-β-cyclodextrin. The balance of the composition will generally be up to 100% water, but additional pharmaceutically acceptable additives such as preservatives, antioxidants, antimicrobial agents, flavoring agents, etc. are known to those skilled in the art. It will be appreciated that they may be added in concentrations. The concentration range of the compound of formula I is 1-30% w / v, for example 10-20% w / v and 12-18% w / v.
Are preferred, more preferably 0.5-5% w / v, most preferably 1-3% w / v.
v. The concentration range of 2-hydroxypropyl-β-cyclodextrin is 20
-50% w / v is preferable, and 30-40% w / v is more preferable.

Particularly preferred embodiments of the present invention include: a) (R) -7- [1- (4-chlorophenoxy) ethyl] -1,2,4 at a concentration ranging from 0.1 to 30% w / v. A pharmaceutical composition in the form of an aqueous solution comprising -triazolo [1,5-a] pyrimidine; and b) 2-hydroxypropyl-β-cyclodextrin at a concentration in the range of 5 to 75% w / v. (R) -7- [1- (4-
The concentration of [chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine is preferably 1-30% w / v (e.g. 10-20%, most preferably w / v 12-18% w / v). / V), more preferably 0.5-5% w / v, most preferably 1-3% w / v.

The concentration of 2-hydroxypropyl-β-cyclodextrin is 20-50% w /
v is preferable, and 30 to 40% w / v is more preferable.

The efficacy of the composition of the present invention was demonstrated by the following test.

[0044]Method  i) Middle cerebral artery (MCA) occlusion  Male Sprague-Dawley rats (300-350 g) were treated with oxygen (10
(00 ml / min). Anesthesia is triggered with 5% (v / v) halothane
The concentration was maintained at 2.25-2.5% using a facial mask. Thermostat system
Maintain the temperature of the animals during surgery using a heated surgical blanket at 37 ° C ± 0.5 ° C.
I carried it. A scalp incision was made at the midpoint between the right eye and the right ear. Separate the temporal muscles in the plane of the fiber bundle
Press down to expose cheekbones and squamous bones. Scrape muscle and connective tissue from bone
The tip of the tool was positioned. Using microsurgical techniques, no. 5 circular head dental bur
A cranial craniotomy was used to open the fusion point of the two skulls. Does not cause thermal damage to brain skin
The skull was cooled by regularly applying sterile saline as described above. Tip of 25g hypodermic needle
Bend in a hook shape to incise the dura mater and buffy coat, and gently tweeze from the cortical surface
I pulled it out. Bipolar diathermy (GU Manufacturing Compa)
ny, London) using the arteries below the olfactory sulcus and to the parietal and frontal cortical branches
The exposed middle cerebral artery at a second point below the bifurcation was electroablated. Bleeding due to MCA obstruction
Animals that were removed from the study. MCA dissected at both points with a pair of microscissors
And ensured separation of the blood vessels. Be careful to avoid nonspecific damage to the surface of the cerebral cortex
did. Finally, the temporalis muscle and the skin thereon were returned to their original positions and sutured. After surgery, suck
Put the animal in the cage on the paper collection and recover consciousness while warming mildly from the red 60W light bulb
I let it. After recovery, the animals were kept in cages and divided into groups (n = 4-6). Surgery
The time is 15 to 20 minutes, and the animal must be conscious within 10 to 15 minutes after the occlusion.
Restored.

[0045]ii) Drug manufacturing  First, two different cyclodextrins (Research Biochemi)
cals Inc. ) Ie 2-hydroxypropyl-β-cyclodextrin and
(-)-7- [1- (4-Chloro) using methyl-β-cyclodextrin
Phenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine (hereinafter
Below, referred to as the test compound). Dissolve test compound in each cyclodextrin
Solution (35% w / v aqueous solution) and sonicated water bath so that the temperature of the solution does not rise
For 5-10 minutes. The compound is 2-hydroxypropyl-β-cyclode
15 mg / ml (i.e., 0.1 to 15 mg / ml) in a xytrin solution,
-Soluble up to an estimated concentration of 40 mg / ml in cyclodextrin. Methyl
-Β-cyclodextrin was not used in animals due to the inability of the animals to tolerate intraperitoneal injections.
Droxypropyl-β-cyclodextrin was selected for testing.

[0046]iii) Animal treatment  MCA occlusion + test compound (n = 11) and MCA occlusion + vehicle (n = 12)
Two groups of animals were used. Animals were weighed immediately before MCA occlusion and 6 days after recovery.
Was. Test compound in sterile saline 35% w / v 2-hydroxyp in sonicated water bath
It was dissolved in ropyl-β-cyclodextrin to a concentration of 15 mg / ml. Behiku
The pH of the drug and drug solutions was adjusted to 7.4 and stored at 4 ° C. for the duration of the experiment. MCA's
60 minutes after coagulation and cleavage, 35 mg / kg of test compound or equivalent volume of vehicle
Animals were injected intraperitoneally. Thereafter, 20 mg /
kg was administered to the animals.

[0047]iv) Histopathological test for ischemic injury  Six days after recovery, the animals were sagital (85 mg / kg ip, Rho
ne Merieux) and cold (4 ° C.) phosphate buffered saline (Oxoid)
For 3 minutes, then with cold 4% formaldehyde in phosphate buffered saline (pH 7.4)
Transcardiac perfusion for 15 minutes. Brain was removed and immersed and fixed at 4 ° C for at least 48 hours
.

Vibratome (General Scientific, Series 10
(00), the brain was cut in the coronal plane at 250 μm intervals and 30 μm thickness. B
Ischemic on 13 faces at 500 μm intervals from +2.7 mm to -3.3 mm for leguma
The extent of damage was examined. Slide glass to slide glass Schaukasten (Car
1 Zeiss; 17.5 times) to show the damaged area on the brain coordinate map. Lesion
The area was measured with a SeeScan image analyzer and the lesion volume was computer analyzed (G
(RaphPad Prism). Without telling the operator how to proceed
All sections were recorded and lesion size was measured.v) Statistical analysis of data  Tissue damage tests and rat body weight changes were analyzed using a two-way ANOVA. All day
Data are expressed as mean ± standard deviation.

[0049]result  Animals show no severe nerve damage such as seizures or hemiparesis due to MCA occlusion and
Animals treated with test compound show weak sedation, especially in the first 5-6 hours after initial administration
Was. Two out of a total of 25 rats were incompletely closed with MCA by electrocoagulation.
He died shortly after recovery from anesthesia due to bleeding. Inject vehicle or test compound
None of the animals fed died.

[0050]i) Histopathological damage after MCA occlusion  Ischemic damage in brain sections stained with toluidine blue is evident as pale areas
A clear demarcation between healthy tissue and injured damage. Due to MCA blockage
Injuries were mainly found in the parietal, islet, frontal and forelimb cortical areas. Outer area of caudate putamen
There was also damage. This is due to the presence of edema in the cortex and corpus callosum, resulting in compression.
Due to the secondary damage. Therefore, the caudate puta distal to the occlusion site
It can be determined that no artery is supplied.

Six days after the ischemic attack, rats receiving the test compound (60 min after MCAO, 3
5 mg / kg ip + 20 mg / kg x 3) reduced the lesion volume by 40% compared to animals receiving vehicle alone. Lesion volume rats treated with vehicle 72.0 ± 7.9 mm ^3, animals were 43.6 ± 4.9 mm ³ dosed with test compound.

As a comparative test, a suspension of the test compound was administered to rats by oral gavage (M
15 minutes after CAO, 50 mg / kg x 3). The test compound reduced the lesion volume by 31% compared to the vehicle-administered control (82.6 ± 6.47 mm ³ ) (56.9).
± 6.1 mm ³ ).

As is clear from the above results, the composition of the present invention is more advantageous than conventionally known compositions. In particular, solutions of the compound of formula I are advantageous over suspensions, ie, administration of lower doses at a later time after MCA occlusion has a greater effect on reducing lesion volume. The solution formulations of the present invention may also solve the problem of compounds of formula I having a short half-life in humans. In addition, such solution formulations can be administered by continuous intravenous infusion, which is particularly beneficial in treating stroke.

Hereinafter, the present invention will be described by way of examples only. The final product of each of the examples was characterized by gas-liquid chromatography, high performance liquid chromatography, elemental analysis, nuclear magnetic resonance spectroscopy and infrared spectroscopy.

Other compounds of the invention are described in WO 95/105, which is incorporated herein by reference.
21 (Knoll AG) and WO 98/07724 (Knoll AG). Cyclodextrin may be a commercially available product, or Chemical Reviews (1998), which is incorporated herein by reference.
) 98, 1474-2076.

[0056]Example 1  1a) 2- (4-Chlorophenoxy) propionic acid in toluene (300 ml)
(30.0 g) was mixed with thionyl chloride (22.0 ml) and dimethylformamide.
To a toluene (150 ml) solution at 60-70 ° C. with stirring.
The mixture was stirred at 70-80 ° C. for 18 hours and then evaporated under reduced pressure to obtain the acid chloride.
A solution of Meldrum's acid (23.5 g) in dichloromethane (90 ml) was added under nitrogen under a nitrogen atmosphere.
After cooling to 5 ° C, pyridine (33 ml) was added at 0-5 ° C. Temperature below 5 ° C
While maintaining, dissolve the acid chloride prepared as above in dichloromethane (90 ml).
The liquid was added dropwise to this mixture. The mixture is left at 0-5 ° C. for 1 hour and then at ambient temperature for 18 hours.
Stirred for hours. Dilute the mixture with dichloromethane (150 ml), add 2M hydrochloric acid,
Washed with a sodium bicarbonate solution and water sequentially. Acidify bicarbonate wash with 5M hydrochloric acid
And extracted with dichloromethane. These dichloromethane extracts are combined with the original dichloromethane
It was combined with a dichloromethane solution and evaporated to dryness to obtain a crude intermediate Meldrum acid derivative. This invitation
The conductor was boiled under reflux of methanol (400 ml) for 6 hours, and then hydrogen chloride methanol
Solution (10 ml) was added and allowed to cool to ambient temperature over 66 hours. The mixture
Evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. Separate the ethyl acetate layer and saturate
After washing with sodium bicarbonate solution and brine, it was evaporated to dryness under reduced pressure to give
The oil was distilled under high vacuum. Petroleum ether / ethyl acetate with a melting point of 60-80 ° C
Flash column chromatography on silica, using 20: 1 as mobile phase
When the fraction is purified by means of 4- (4-chlorophenoxy) -3-oxopentane
Methyl acid was obtained as an oil.

B) Guanidine hydrochloride (sodium (0.41 g) in ethanol (15 ml)
1.87 g) were added with stirring. After stirring the mixture for 15 minutes, 4
A solution of methyl-(4-chlorophenoxy) -3-oxopentanoate (5.0 g) in ethanol (15 ml) was added. The mixture was stirred and boiled under reflux for 16 hours. After cooling the mixture was evaporated to dryness under reduced pressure to give a solid. Glacial acetic acid (2 ml) and dichloromethane (20 ml) were added to water (10 ml), and the solid was triturated for 1 hour and filtered. The obtained residue was washed with water (20 ml) and then with dichloromethane to obtain 2-amino-4- [1- (4-chlorophenoxy) ethyl-6-hydroxypyrimidine (mp 125 ° C.).

C) 2-amino-4- [1- (4-chlorophenoxy) ethyl-6-hydroxypyrimidine (0.5 g), dimethylformamide dimethyl acetal (0.5
ml) and toluene (5 ml) was stirred and boiled under reflux for 8 hours. The mixture was evaporated for 8 hours. After allowing the mixture to cool to ambient temperature over 24 hours,
Evaporation to dryness under reduced pressure, trituration of the resulting solid with ether and filtration gave amidine as a solid.

D) Dissolve sodium hydride (62 mg dispersion in mineral oil, 62 mg washed with gasoline to remove mineral oil) in methanol (10 ml) and add hydroxylamine hydrochloride (0.
12g) was added. After stirring the mixture for 5 minutes, it was added to the amidinopyridine (0.5 g) obtained in c). After stirring the mixture at ambient temperature for 72 hours, it was evaporated to dryness under reduced pressure, the residue obtained was washed with water and dried to give formamidoxin.

E) The product from d) (5.0 g) and polyphosphoric acid (100 g) were stirred and heated in a steam bath for 4 hours. After allowing the mixture to cool to ambient temperature, ice (100 g) and ethyl acetate (100 ml) were added. An aqueous solution of potassium carbonate (110 g) (total volume: 100 ml) was added dropwise over 15 minutes to neutralize the mixture. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were dried and evaporated to give a solid which was purified by flash column chromatography on silica using dichloromethane / methanol (75: 3) as mobile phase to give 7- [1- (4- Chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-ol (mp 190 ° C.) was obtained.

[0061]Example 2  (-)-7- [1- (4-Chlorophenoxy) ethyl] -1,2,4-tria
Zolo [1,5-a] pyrimidine was prepared as described in WO 95/10521.
Manufactured.

[0062]

[Table 1]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) // C07D 487/04 146 C07D 487/04 146 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, C , DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL , TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Martin, Keith Frank Nottingham NJ 1.1. G. F., Pennyhut Street R. 3 (72) Inventor Smith, Sialon Leslie, Nottingham N.G. 1.1 G. F., Pennyhut Street R. 3 F. term (reference) ) 4C050 AA01 BB06 CC08 EE04 FF01 FF02 GG01 HH01 4C076 AA12 BB01 BB13 CC01 EE39 FF15 FF68 GG45 GG46 4C086 AA01 AA02 CB08 MA05 MA17 MA52 MA66 NA02 NA03 NA10 ZA06 ZA08 ZA15

Claims (18)

[Claims] 1. a) Formula I: embedded image Wherein R ₁ is H or _one of C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkanoyl groups (optionally substituted with one or more halo, cyano, hydroxy or amino). Wherein R ₂ and R ₃ are independently H or C _1-6 alkyl (optionally substituted with one or more halo, cyano, hydroxy or amino), C _1-6 alkoxy, C _1-6 alkanoyl, Represents one of C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl or a hydroxy group, and R ₄ and R ₅ independently represent H, C _1-6 alkyl, or R ₄ and R ₅ halo when a represents (each alkyl or cycloalkylidene is C _3-6 cycloalkylidene together with the carbon atoms to which they are attached together, cyano, hydroxy
R ₆ , R ₇ and R ₈ may be independently H, halo, hydroxy, mercapto, nitro, cyano or (optionally halo, cyano), optionally substituted with one or more amino or C _1-6 alkyl. , hydroxy or substituted amino of 1 or more, when a nitrogen atom present is substituted with one or more C _{1 -6} alkyl optionally nitrogen atom) C _1-6 alkyl, C _{1 -6 alkanoyl, C 1-6 alkoxy, C 2-6} alkoxycarbonyl, _{carboxy, C 1-6 alkanoyloxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6} alkylsulfonylamino, sulfamoyl, _carbamoyl, a _{C 2-6} 1 or alkylcarbamoyl or _{C 1-6} alkanoylamino group table Compounds of] and (a pharmaceutically acceptable salt, solvate, racemate, enantiomer, diastereoisomer including isomers and mixtures thereof), b) pharmaceutical compositions containing cyclodextrins. 2. The composition according to claim 1, wherein the composition is a mixture of a compound of the formula I and cyclodextrin. 3. The composition according to claim 1, wherein the composition comprises a complex of the compound of formula I and cyclodextrin. 4. A compound of the formula I wherein 7- [1- (4-fluorophenoxy) ethyl] -1,2,4-triazolo [1
, 5-a] pyrimidine, 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,
5-a] pyrimidine, 7- [1- (4-bromophenoxy) ethyl] -1,2,4-triazolo [1,
5-a] pyrimidine, 7- [1- (4-cyanophenoxy) ethyl] -1,2,4-triazolo [1,
5-a] pyrimidine, 7- [1- (4-trifluoromethylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-methoxyphenoxy) ethyl ] -1,2,4-triazolo [1
, 5-a] Pyrimidine, 7- [1- (4-trifluoromethoxyphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-acetylphenoxy) Ethyl] -1,2,4-triazolo [1
, 5-a] pyrimidine, 7- {1- [4- (methylthio) phenoxy] ethyl} -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-methylsulfinylphenoxy) ) Ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-methylsulfonylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine 7- {1- [4- (ethylthio) phenoxy] ethyl} -1,2,4-triazolo [1,5-a] pyrimidine; 7- [1- (3-chlorophenoxy) ethyl] -1,2 , 4-triazolo [1,
5-a] pyrimidine, 7- [1- (2,4-difluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (2,4-dichlorophenoxy) ) Ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (3,4-dichlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] Pyrimidine, 7- [1- (2-chloro-4-fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-chlorophenoxy) ethyl]- 2-methyl-1,2,4-triazolo [1,5-a] pyrimidine, 7- (4-chlorophenoxymethyl) -1,2,4-triazolo [1,5-a]
Pyrimidine, 7- [1- (4-chlorophenoxy) -1-methylethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-chlorophenoxy) propyl]- 1,2,4-triazolo [1
, 5-a] pyrimidine and 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,
The composition according to any one of claims 1 to 3, wherein the composition is selected from 5-a] pyrimidin-5-ol and its stereoisomers and pharmaceutically acceptable salts thereof. 5. A compound of formula I wherein (+)-7- [1- (4-fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, (-)-7 -[1- (4-fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, (+)-7- [1- (4-chlorophenoxy) ethyl] -1,2 , 4-Triazolo [1,5-a] pyrimidine, (−)-7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, (+) -7- [1- (4-Chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-ol, and (-)-7- [1- (4-chlorophenoxy) ) Ethyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-ol and The composition according to any one of claims 1 to 4, wherein the composition is selected from pharmaceutically acceptable salts thereof. 6. The compound of formula I is (R) -7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine.
The composition according to any one of claims 1 to 5. 7. A composition according to claim 1, which is in the form of an aqueous solution containing a) a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 6 and b) cyclodextrin. Composition. 8. The composition according to claim 1, wherein the cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin. 9. The composition according to claim 1, wherein the cyclodextrin is β-cyclodextrin. 10. The composition according to claim 9, wherein the cyclodextrin is methyl-β-cyclodextrin or 2-hydroxypropyl-β-cyclodextrin. 11. The composition according to claim 9, wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. 12. A compound of formula I according to any one of claims 1 to 6 comprising: a) a therapeutically effective amount of a compound ranging from 0.1 to 30% w / v; and b) 5 ~ 75
The composition according to claim 1, which is in the form of an aqueous solution containing 2-hydroxypropyl-β-cyclodextrin at a concentration in the range of% w / v. 13. The composition according to claim 12, wherein the compound of formula I is present in a concentration ranging from 1 to 3% w / v. 14. The composition according to claim 12, wherein the concentration of 2-hydroxypropyl-β-cyclodextrin ranges from 30 to 40% w / v. 15. The composition according to any one of claims 1 to 14, which is an oral composition. 16. The composition according to claim 12, which is a composition for intravenous injection. 17. A neuroprotective agent for suppressing neurological disorders such as seizures and / or epilepsy in animals including humans and / or preventing conditions such as stroke, brain trauma, head trauma and bleeding. Use of the composition according to any one of items 1 to 16. 18. Use of a composition according to any one of claims 1 to 16 in the treatment and prevention of migraine.